RAndomized Clinical Trial Of NAfamostat Mesylate, A Potent Transmembrane Protease Serine 2 (TMPRSS2) Inhibitor, in Patients with COVID-19 Pneumonia

Abstract

Even though SARS-CoV-2 was declared by WHO as constituting no longer a public health emergency, the development of effective treatments against SARS-CoV-2 infection remains a critical issue to prevent complications, particularly in fragile patients. The protease inhibitor nafamostat, currently used in Japan and Korea for pancreatitis, owing to its anticoagulant properties for disseminated intravascular coagulation (DIC), is appealing for the treatment of COVID-19 infection, because it potently inhibits the transmembrane protease serine 2 (TMPRSS2) that, after virus binding to ACE-2, allows virus entry into the cells and replication. Moreover, it could prevent the DIC and pulmonary embolism frequently associated with COVID-19 infection. The goal of the RAndomized Clinical Trial Of NAfamostat (RACONA) study, designed as a prospective randomized, double-blind placebo-controlled clinical trial, was to investigate the efficacy and safety of nafamostat mesylate (0.10 mg/kg/h iv for 7 days), on top of the optimal treatment, in COVID-19 hospitalized patients. We could screen 131 patients, but due to the predefined strict inclusion and exclusion criteria, only 15 could be randomized to group 1 (n = 7) or group 2 (n = 8). The results of an ad interim safety analysis showed similar overall trends for variables evaluating renal function, coagulation, and inflammation. No adverse events, including hyperkalemia, were found to be associated with nafamostat. Thus, the RACONA study showed a good safety profile of nafamostat, suggesting that it could be usefully used in COVID-19 hospitalized patients.

Keywords: COVID-19; SARS-CoV-2; coagulation; nafamostat mesylate; safety; transmembrane protease serine 2 TMPRSS2.

Figure 1

Serum sodium (A) and potassium levels (B), and systolic (SBP) (C) and diastolic blood pressure (DBP) (D) in patients receiving treatment 1 (nafamostat) or treatment 2 (placebo). Blinded codes were disclosed after the safety analysis. * p = 0.02, ** p = 0.01, *** p = 0.001, vs. group 1.

Figure 2

The pO₂/FiO₂ (A), SaO₂ levels (B), SOFA score (C), and respiratory rate (D) in patients receiving treatment 1 (nafamostat) or treatment 2 (placebo). Blinded codes were disclosed after the safety analysis. SOFA: Sequential Organ Failure Assessment (including PaO₂, FiO₂, mechanical ventilation, platelet counts, Glasgow Coma Scale, Bilirubin, MAP, S-creatinine); * p = 0.03; ** p = 0.02 vs. group 1.

Figure 3

Serum levels of ALT (A), AST (B), C-reactive protein (C), and platelet count (D) in patients receiving treatment 1 (nafamostat) or treatment 2 (placebo). Blinded codes were disclosed after the safety analysis. * p = 0.01, ** p = 0.02, vs. group 1.

Figure 4

Posterior and prior distributions (blue curve is with penalization for over-optimism and the red curve is without it). The plots refer to the probability that the treatment is effective (i.e., ${\pi }_{control}-{\pi }_{treat}$ is less than reported) under three scenarios of prior information (Informative, Informative with adjustment for optimism, and Uninformative). Probabilities are ${\pi }_1= {\pi }_{control}$ and ${\pi }_2= {\pi }_{treat}$.